Putative mechanisms of ocular inflammation in syphilis.

BACKGROUND: Ocular syphilis is re-emerging globally as a cause of uveitis, with the potential for substantial vision loss. Multimodal ophthalmic imaging and advanced laboratory research can yield important information about the basic mechanisms of this infectious eye disease. REVIEW: Inflammation of the retina is a frequent manifestation of ocular syphilis. Observations from multimodal ophthalmic imaging suggest the retinal pigment epithelium and retinal vasculature are often involved. Molecular profiling of biopsies from patients with syphilis involving the eye and brain indicates multiple leucocyte subsets infiltrate the posterior eye, and highlights the role of monocytes and macrophages in promoting inflammation. Aqueous and cerebrospinal fluid samples from patients with ocular syphilis contain high levels of inflammatory mediators, including C-C motif chemokine ligand (CCL) 2, C-X-C motif chemokine ligand (CXCL) 8, interleukin (IL)-6, IL-12, and tumour necrosis factor (TNF). Macrophages and dendritic cells exposed to the causative bacterium, Treponema pallidum, increase the production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF. Toll-like receptor activation and nuclear factor of kappa light chain enhancer of B-cells (NFκB) signalling in non-ocular human cells play prominent roles in upregulating inflammatory molecules, and altering interactions between leucocytes and epithelial or endothelial cells; similar cellular and molecular changes at the outer and inner blood-retinal barriers could contribute to retinal inflammation in ocular syphilis. Experimental evidence also indicates that T. pallidum alters intercellular junctions and transmigrates endothelial cell monolayers, potentially mediating retinal invasion. CONCLUSIONS: Evidence from multimodal ophthalmic imaging, molecular profiling in patients, and non-ocular cell infection models provides essential insights into the pathogenesis of ocular syphilis. This knowledge will target future research towards elucidating the drivers of retinal inflammation in ocular syphilis.